Serotonin, a neurotransmitter with mixed and complex pharmacological characteristics, was first discovered in 1948, and subsequently has been the subject of substantial research. Serotonin, also referred to as 5-hydroxytryptamine (5-HT), acts both centrally and peripherally on discrete 5-HT receptors. Currently, fourteen subtypes of serotonin receptor are recognized and delineated into seven families, 5-HT.sub.1, to 5-HT.sub.7. Within the 5-HT.sub.2 family, 5-HT.sub.2A, 5-HT.sub.2B, and 5-HT.sub.2C subtypes are known to exist. These subtypes share sequence homology and display similarities in their specificity for a wide range of ligands. Nomenclature and classification of 5-HT receptors have been reviewed recently (see Martin and Humphrey, Neuropharm. 1994, 33, 261-273 and Hoyer et al., Pharm. Rev. 1994, 46, 157-203).
The 5-HT.sub.2B receptor, initially termed 5-HT.sub.2F, or serotonin-like receptor, was first characterized in rat isolated stomach fundus (see Clineschmidt et al., J. Pharmacol. Exp. Ther. 1985, 235, 696-708; Cohen and Wittenauer, J. Cardiovasc. Pharmacol. 1987, 10, 176-181). The 5-HT.sub.2C receptor, widely distributed in the human brain, was first characterized as a 5-HT.sub.1C subtype (see Pazos et al., Eur. J. Pharmacol. 1984, 106, 539-546) and was subsequently recognized as belonging to the 5-HT.sub.2 receptor family (see Pritchett et al., EMBO J. 1988, 7, 4135-4.140).
Because of the similarities in the pharmacology of ligand interactions at 5-HT.sub.2B and 5-HT.sub.2C receptors, many of the therapeutic targets that have been proposed for 5-HT.sub.2C receptor antagonists are also targets for 5-HT.sub.2B receptor antagonists. Current evidence strongly supports a therapeutic role for 5-HT.sub.2B/2C receptor antagonists in treating anxiety (e.g., generalized anxiety disorder, panic disorder and obsessive compulsive disorder), alcoholism and addiction to other drugs of abuse, depression, migraine, sleep disorders, feeding disorders (e.g., anorexia nervosa) and priapism. Additionally, current evidence strongly supports a therapeutic role for selective 5-HT.sub.2B receptor antagonists that will offer distinct therapeutic advantages collectively in efficacy, rapidity of onset and absence of side effects. Such agents are expected to be useful in the treatment of hypertension, disorders of the gastrointestinal track (e.g., irritable bowel syndrome, hypertonic lower esophageal sphinter, motility disorders), restenosis, asthma and obstructive airway disease, and prostatic hyperplasia (e.g., benign prostatic hyperplasia).
Numerous aryl substituted pyrimidine compounds have been exemplified in the chemical and patent literature. For example, Budesinsky et al., Collection Czechoslav. Chem. Commun. 1961, 26, 2865-2870, disclose 2-amino-6-methyl-4-(naphth-1-yl)-pyrimidine as an intermediate useful in the preparation of antibacterial compounds. Other pyrimidine derivatives are described in Mariella et al., J. Org. Chem. 1960, 25, 647-648; Zagulyaeva et al., Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk 1990, 4, 27-31; Essawy et al., Egypt. J. Chem. 1994, 37(4), 423-31; U.S. Pat. Nos. 4,543,248, 4,619,933, 4,665,077, and 5,002,951, all to Stringfellow et al.; U.S. Pat. No. 5,147,876 to Mizuchi et al.; U.S. Pat. No. 5,223,505 to Hargreaves et al.; and European Patent Published Application EP 0 459 830, assigned to the Wellcome Foundation.
The disclosures of these and other documents referred to throughout this application are incorporated herein by reference.